Evaluation of the Efficacy of LevetiracetamPlus Iron in Comparison With Iron Alone in Controlling and Reducing the Frequency of Breath-Holding Spells in Children Aged 6 Months to 5 Years

Objective A breath-holdingspell (BHS) is defined as an apnea attack following an initial stressful event like anger, sadness, and fear, a painful event like falling or head trauma or any stressful psychology event. This study was designed to assessthe comparative efficacy of levetiracetam plus iron and iron alone in reducingthe BHS frequency in children aged 6 months to 5 years. Materials &Method This study was designed asa double-blinded randomized clinical trial. Sixty patients aged 6 months to 5 years were assigned into two groups, withthe first group (A) receiving onlyiron and the second group (B)receiving levetiracetam plus iron. At the end of the study, the efficacy of therapywas analyzed comparatively in these groups. Results In this study, the mean number of attacks was 3.94 ± 2.69 before treatment and 1.71 ± 1.99after treatmentin the group A,while it was 6.39 ± 5.7 before treatment and 0.37 ± 1.03after treatment in the group B.The mean number of attacksafter treatment was lower in group B than in group A. In fact, there was a significant difference between the two groups in terms of the number of attacks after treatment (P = 0.003). Conclusion Levetiracetam plus iron is more effective than iron alone in reducing BHSs in children aged 6 months to 5 years.


Introduction
A breath-holding spell (BHS) is defined as an attack following an initial stressful event such as anger, grief, and fear, a painful stimulus such as falling and head trauma, or any other psychological distress (1,2). During these attacks, the child starts crying in less than 11 seconds of initial stress, and after a deep inhalation, stops breathing in the exhalation stage, causing facial changes of either cyanosis or pallor. Attacks are sudden and involuntary with benign and self-limited nature, but careful consideration should be given to rule out any serious problem (3,4).
The age of the onset of BHS is 11.6 months.
However, it may occur before 6 months, and in about 11% of cases, the first attack occurs after 2 years of age. Attacks decrease after 2 years of age, and until the age of 4, 11% of children will be attack free; almost all patients will recover by the age of 7. In the majority of articles, the gender of children studied showed a male to female ratio of more than one (5).
The pathophysiology of attacks is a complicated process and is not yet fully discovered. Various studies have been conducted to examine the exact cause and the nature of attacks, and each of them presented a separate mechanism. Some studies on the pathophysiologic mechanism suggested that the underlying cause of breath-holding attacks was the irregularity of the autonomic nervous system (6,7). In one study on the autonomic nervous system activity, ECG changes such as heart rate, frequency, and length of QT interval during an attack were recorded. The presence of disorders of the respiratory sinus rhythm and long systole was noticed during the attack, indicating the presence of a disorder in the regulation of the autonomic nervous system (8).
Iron deficiency is the most common cause of anemia in the first 2 years of life, a period which can be observed as the BHS peak in children. Some studies have shown that anemia or low levels of red blood cells may be an etiologic factor, and iron supplements may improve BHS in children (9)(10)(11). Levetiracetam is a new antiepileptic drug that is structurally similar to piracetam, which has been used in the treatment of BHSs. Previous studies have suggested that piracetam is an anxiety stabilizing agent, and thus, improves BHSs (12, 13). Levetiracetam has fast and complete digestive absorption, but its protein binding is small. The drug and its metabolites are excreted through the urine and have a half-life of about 6-8 hours. The drug does not interact with other antiepileptic drugs, and also, does not affect the pharmacokinetics of other drugs such as contraceptive drugs, digoxin, and warfarin. It is used as an adjunct to control general and partial epilepsy. The exact mechanism of levetiracetam is still unknown, but its side effects are extremely small and do not require any controlled testing (14,15). According to limited reports regarding the use of new pharmacological methods and the traditional method of using an iron to control BHSs, we designed and implemented this study to evaluate the efficacy of levetiracetam in combination with iron supplementation compared with iron therapy alone in controlling BHSs.

Materials & Method
In this randomized clinical trial, 60 6-month to The patients were randomly assigned into two groups: the first group (A) received only iron supplement at a dose of 5 mg/kg/day (from ferrous sulfate in two divided doses) for three months and the second group (B) started levetiracetam at a dose of 10 mg/kg/ day titrating to 40 mg/ kg/day (at two doses of Cobel Darou company) and iron at a dose of 5 mg/kg/day (from ferrous sulfate in two divided doses) for three months. All information needed for the research about age, sex, and number of attacks before and after treatment was gathered monthly through follow-up visits and over telephone and entered in checklists for final analysis. The data were analyzed using SPSS version 22 and reported using descriptive statistics (frequency and percentage) and mean ± standard deviation (mean ± SD). A Student's t-test was used to analyze quantitative data and the Chi-square test to analyze the qualitative variables (and Fisher's exact test if required). The data were also evaluated using the Kymograph-Smirnov test. The ANOVA test was used in case the data distribution was normal, and the Mann-Whitney U test was used to analyze non-parametric data. P-value <0.05 was considered statistically significant.  (Tables 1 and   2). There was no significant difference between the two groups regarding age, HB, and ferritin based on the Mann-Whitney U non-parametric test results (Table 2).

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Group A consisted of 17 boys and 11 girls compared to group B with 11 boys and 21 girls, making an overall of 28 boys and 32 girls (Table 3-

In Conclusion
Based on the findings of our study, we suggest that the combination of levetiracetam and iron is more effective than iron alone in controlling BHSs.
Being a safe pharmaceutical profile in children, levetiracetam can be safely used to control BHS in combination with iron.

Acknowledgment
We would like to thank the patients' parents for their cooperation in this investigation.

Author's contribution
Abasi E: Were responsible for the study design and interpretation of clinical data.
Ghazavi A: Supervised the study, revised and edited the manuscript.
Mohamad Vand Matinkhah M: collected the data.
Hassanvand Amouzadeh M: Wrote the first draft of this manuscript.
All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the